Leukocyte RhoA exchange factor Arhgef1 mediates vascular inflammation and atherosclerosis.

Abnormal activity of the renin-angiotensin-aldosterone system plays a causal role in the development of hypertension, atherosclerosis, and associated cardiovascular events such as myocardial infarction, stroke, and heart failure. As both a vasoconstrictor and a proinflammatory mediator, angiotensin II (Ang II) is considered a potential link between hypertension and atherosclerosis. However, a role for Ang II-induced inflammation in atherosclerosis has not been clearly established, and the molecular mechanisms and intracellular signaling pathways involved are not known. Here, we demonstrated that the RhoA GEF Arhgef1 is essential for Ang II-induced inflammation. Specifically, we showed that deletion of Arhgef1 in a murine model prevents Ang II-induced integrin activation in leukocytes, thereby preventing Ang II-induced recruitment of leukocytes to the endothelium. Mice lacking both LDL receptor (LDLR) and Arhgef1 were protected from high-fat diet-induced atherosclerosis. Moreover, reconstitution of Ldlr-/- mice with Arhgef1-deficient BM prevented high-fat diet-induced atherosclerosis, while reconstitution of Ldlr-/- Arhgef1-/- with WT BM exacerbated atherosclerotic lesion formation, supporting Arhgef1 activation in leukocytes as causal in the development of atherosclerosis. Thus, our data highlight the importance of Arhgef1 in cardiovascular disease and suggest targeting Arhgef1 as a potential therapeutic strategy against atherosclerosis.

Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice: Implications for Superficial Erosion.

RATIONALE: Superficial erosion currently causes up to a third of acute coronary syndromes; yet, we lack understanding of its mechanisms. Thrombi because of superficial intimal erosion characteristically complicate matrix-rich atheromata in regions of flow perturbation. OBJECTIVE: This study tested in vivo the involvement of disturbed flow and of neutrophils, hyaluronan, and Toll-like receptor 2 ligation in superficial intimal injury, a process implicated in superficial erosion. METHODS AND RESULTS: In mouse carotid arteries with established intimal lesions tailored to resemble the substrate of human eroded plaques, acute flow perturbation promoted downstream endothelial cell activation, neutrophil accumulation, endothelial cell death and desquamation, and mural thrombosis. Neutrophil loss-of-function limited these findings. Toll-like receptor 2 agonism activated luminal endothelial cells, and deficiency of this innate immune receptor decreased intimal neutrophil adherence in regions of local flow disturbance, reducing endothelial cell injury and local thrombosis (P<0.05). CONCLUSIONS: These results implicate flow disturbance, neutrophils, and Toll-like receptor 2 signaling as mechanisms that contribute to superficial erosion, a cause of acute coronary syndrome of likely growing importance in the statin era.

Long-Term Outcomes of Common Femoral Artery Stenting.

BACKGROUND: The purpose of this study was to report the 5-year outcome relative to endovascular repair of the common femoral artery (CFA) for occlusive disease. METHODS: Thirty-six consecutive patients (40 limbs) underwent stenting for CFA lesions. Patients were followed up systematically within a prospectively maintained database over 5 years. Follow-up included clinical examination, duplex scan, and biplane X-ray at 1, 6, 12 months and yearly thereafter. RESULTS: Indications for endovascular repair of the CFA included 25 patients (70%) for claudication and 11 patients (30%) for critical limb ischemia. Mean follow-up was 64 months. Two patients were lost to follow-up. The mortality rate at 5 years was 38%. At 3 and 5 years, primary sustained clinical improvements were 77% and 73%, respectively. In-stent restenosis rate was 28%. The significant predictors of in-stent restenosis were deep femoral artery stenting (P = 0.0007) and type III lesions (P = 0.014). Freedom from target lesion revascularization and target extremity revascularization were 79% and 73%, respectively. One stent fracture was noted at the first year follow-up without clinical consequence, and no other stent fracture was noted during the remainder of the study. CONCLUSIONS: Endovascular repair of the CFA and its bifurcation seems to provide sustained clinical and morphological long-term results. Fear of stent fracture and local complications due to hip mobility are no longer relevant.